Affiliation: Department of Surgical and Morphological Sciences, University of Insubria, 21100 Varese, Italy.

ABSTRACTCellular microenvironment plays a critical role in several pathologies including atherosclerosis. Hyaluronan (HA) content often reflects the progression of this disease in promoting vessel thickening and cell migration. HA synthesis is regulated by several factors, including the phosphorylation of HA synthase 2 (HAS2) and other covalent modifications including ubiquitination and O-GlcNAcylation. Substrate availability is important in HA synthesis control. Specific drugs reducing the UDP precursors are able to reduce HA synthesis whereas the hexosamine biosynthetic pathway (HBP) increases the concentration of HA precursor UDP-N-acetylglucosamine (UDP-GlcNAc) leading to an increase of HA synthesis. The flux through the HBP in the regulation of HA biosynthesis in human aortic vascular smooth muscle cells (VSMCs) was reported as a critical aspect. In fact, inhibiting O-GlcNAcylation reduced HA production whereas increased O-GlcNAcylation augmented HA secretion. Additionally, O-GlcNAcylation regulates HAS2 gene expression resulting in accumulation of its mRNA after induction of O-GlcNAcylation with glucosamine treatments. The oxidized LDLs, the most common molecules related to atherosclerosis outcome and progression, are also able to induce a strong HA synthesis when they are in contact with vascular cells. In this review, we present recent described mechanisms involved in HA synthesis regulation and their role in atherosclerosis outcome and development.

fig2: Schematic representation of the regulation of HA synthesis by AMPK in SMCs. Through the action of compounds such as AICAR, metformin, and resveratrol or by sensing ATP : AMP ratio or by the action of AMPK upstream kinases (AMPKK), AMPK phosphorylates HAS2 threonine 110 residue inhibiting HAS2 activity and reducing the HA production.

Mentions:
AMPK has a pivotal role in regulating energy homeostasis in eukaryotic cells. In response to a decrease in cellular ATP levels, AMPK reduces the rate of anabolic pathways (ATP-utilizing) and increases the rate of catabolic pathways (ATP-producing) [42]. Through the capacity to detect the ATP : AMP ratio, AMPK acts as a metabolic master switch and phosphorylates key target proteins that control flux through metabolic pathways in order to maintain energy homeostasis. HAS2 is a substrate of AMPK, which phosphorylates threonine 110 to inhibit HAS2 enzymatic activity [38]. Interestingly, AMPK does not alter the synthesis of other GAGs secreted by VSMCs, highlighting the specificity of AMPK action on HA synthesis. This aspect could explain the vasoprotective effect of AMPK activation, obtained also by the antidiabetic drug metformin, to reduce neointima formation in animal models for atherosclerosis [43] (Figure 2).

fig2: Schematic representation of the regulation of HA synthesis by AMPK in SMCs. Through the action of compounds such as AICAR, metformin, and resveratrol or by sensing ATP : AMP ratio or by the action of AMPK upstream kinases (AMPKK), AMPK phosphorylates HAS2 threonine 110 residue inhibiting HAS2 activity and reducing the HA production.

Mentions:
AMPK has a pivotal role in regulating energy homeostasis in eukaryotic cells. In response to a decrease in cellular ATP levels, AMPK reduces the rate of anabolic pathways (ATP-utilizing) and increases the rate of catabolic pathways (ATP-producing) [42]. Through the capacity to detect the ATP : AMP ratio, AMPK acts as a metabolic master switch and phosphorylates key target proteins that control flux through metabolic pathways in order to maintain energy homeostasis. HAS2 is a substrate of AMPK, which phosphorylates threonine 110 to inhibit HAS2 enzymatic activity [38]. Interestingly, AMPK does not alter the synthesis of other GAGs secreted by VSMCs, highlighting the specificity of AMPK action on HA synthesis. This aspect could explain the vasoprotective effect of AMPK activation, obtained also by the antidiabetic drug metformin, to reduce neointima formation in animal models for atherosclerosis [43] (Figure 2).

Affiliation:
Department of Surgical and Morphological Sciences, University of Insubria, 21100 Varese, Italy.

ABSTRACTCellular microenvironment plays a critical role in several pathologies including atherosclerosis. Hyaluronan (HA) content often reflects the progression of this disease in promoting vessel thickening and cell migration. HA synthesis is regulated by several factors, including the phosphorylation of HA synthase 2 (HAS2) and other covalent modifications including ubiquitination and O-GlcNAcylation. Substrate availability is important in HA synthesis control. Specific drugs reducing the UDP precursors are able to reduce HA synthesis whereas the hexosamine biosynthetic pathway (HBP) increases the concentration of HA precursor UDP-N-acetylglucosamine (UDP-GlcNAc) leading to an increase of HA synthesis. The flux through the HBP in the regulation of HA biosynthesis in human aortic vascular smooth muscle cells (VSMCs) was reported as a critical aspect. In fact, inhibiting O-GlcNAcylation reduced HA production whereas increased O-GlcNAcylation augmented HA secretion. Additionally, O-GlcNAcylation regulates HAS2 gene expression resulting in accumulation of its mRNA after induction of O-GlcNAcylation with glucosamine treatments. The oxidized LDLs, the most common molecules related to atherosclerosis outcome and progression, are also able to induce a strong HA synthesis when they are in contact with vascular cells. In this review, we present recent described mechanisms involved in HA synthesis regulation and their role in atherosclerosis outcome and development.